Membrane proteins function as mediators for the exchange of material and information across cell membranes as well as converters of electro-osmotic, mechanical, and chemical energy in cells. These proteins are the targets of most pharmacological interventions and their function is related to many diseases. Often the function of membrane proteins is coupled to the membrane environment through mechanical or electrostatic forces. Advances in biomolecular modeling using large parallel computers permit now the in situ simulation of membrane proteins. In this renewal application we suggest five research projects, the first two extending efforts from the past funding period: (i) the investigation of gating in aquaporins and design of aquaporins with novel properties;(ii) the study of tension-mediated gating of the mechonosensitive channel of small conductance, MscS, and identification of the full function of this channel in bacterial cells. Two new projects investigate membrane channels only recently structurally resolved: (iii) the protein conducting channel SecY involved in cellular trafficking of nascent proteins and (iv) a transporter, LacY, importing lactose into cells utilizing the cells'proton motive force. Project (v) seeks to identify the structures of lipoprotein particles, key to human lipid and cholesterol metabolism, by combining a new simulation methodology for the assembly of the particles with experiments on designed lipoproteins.